The Net Effect of Costimulatory Blockers Is Dependent on the Subset and Activation Status of the Autoreactive T Cells

Zhang, Ping; Sun, Deming; Ke, Ya; Kaplan, Henry J.; Shao, Hui

doi:10.4049/jimmunol.178.1.474

Cited by 6 publications

(4 citation statements)

References 33 publications

(34 reference statements)

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“…7b). Comparable results were observed in previous studies using these specific Abs to test the effects of blocking B7‐1 and B7‐2 function on autoreactive T‐cell proliferation 25 . Similar decreases in IL‐2 production from naïve T cells were observed whether L1210 clone 7‐15·6 was pre‐incubated with pOVA, or high concentrations (50 μ m ) of whole OVA (data not shown).…”

Section: Resultssupporting

confidence: 85%

The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen‐presenting cells

et al. 2009

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SummaryMajor histocompatibility complex class II (MHCII) antigen expression is directly correlated with immunogenicity, and inversely correlated with tumorigenicity, in clones of the L1210 murine B lymphoma. Moreover, loss of MHCII expression on human diffuse large B-cell lymphoma is associated with dramatic decreases in patient survival. Thus, the role that MHCII antigens play in the progression of B-cell lymphomas is clinically important. In this study, we investigated the basis for the immunogenicity of MHCII + L1210 clones. Immunogenic, but not tumorigenic L1210clones stimulated the proliferation of naïve T cells and their interleukin (IL)-2 production, which indicates that the immunogenic clones can function as antigen-presenting cells (APCs). However, subclonal variants of the immunogenic L1210 clones, which form tumours slowly in mice, could not activate T cells. The costimulatory molecules B7-1, B7-2 and CD40 were expressed on the immunogenic L1210 clones, but not the tumorigenic clones. Importantly, the tumour-forming subclonal variants expressed MHCII and B7-1, but lacked B7-2 and CD40. These results suggest that MHCII and B7-1 expression on L1210 cells is insufficient to activate naïve T cells, and, furthermore, loss of B7-2 and/or CD40 expression contributes to the decreased immunogenicity of L1210 subclones. Blocking B7-1 or B7-2 function on immunogenic L1210 cells reduced their capacity to activate naïve T cells. Furthermore, incubation of immunogenic L1210 cells with CD40 antibodies significantly enhanced APC function. Therefore, the immunogenicity of L1210 cells directly correlates (i) with their ability to stimulate naïve T cells, and (ii) with the concomitant expression of MHCII, B7-1, B7-2, and CD40.

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Section: Resultssupporting

confidence: 85%

The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen‐presenting cells

et al. 2009

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“…Similar results were obtained when tetramer analysis was performed in relation to endogenous expression of CD40L based on intracellular staining (data not shown). We also investigated whether blocking CD40-CD40L interaction with CD40 blocking antibody (clone, IC10, eBioscience; Zhang et al, 2007;Baker et al, 2008;Otani et al, 2011) during antigenic stimulation can facilitate stabilization of CD40L such that tet + cells can then be Figure 6. Specificity of IA k /Myhc-α 334-352 tetramers created based on peptide-exchange reaction.…”

Section: Binding Of Myhc-α 334-352 Tetramers Do Not Correlate With CDmentioning

confidence: 99%

Detection of cardiac myosin heavy chain-α-specific CD4 cells by using MHC class II/IAk tetramers in A/J mice

Massilamany

Gangaplara

Chapman

et al. 2011

Journal of Immunological Methods

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A/J mice bearing the H-2 allele IA(k) are highly susceptible to autoimmune myocarditis induced with cardiac myosin heavy chain (Myhc)-α 334-352, whereas B10.A mice carrying a similar allele IA(k) are relatively resistant, suggesting that the generation of Myhc-α-reactive T cell repertoires is influenced by genetic background. To enumerate the precursor frequencies of Myhc-α-specific CD4 T cells, we sought to create IA(k) tetramers for Myhc-α 334-352. Tetramers were created using approaches that involve covalent tethering of individual peptide sequences or exogenous loading of peptides into empty IA(k) molecules by peptide-exchange reaction. Using ribonuclease 43-56 tetramers as controls, we demonstrated that by flow cytometry (FC), Myhc-α 334-352 tetramers specifically bind myosin-reactive T cells. CD4 cells isolated from A/J mice immunized with Myhc-α 334-352 were used to optimize conditions for tetramer staining, and neuraminidase treatment prior to tetramer staining permitted the detection of Myhc-α-specific cells ex vivo. The reagents are useful tools for monitoring the frequency of Myhc-α-reactive CD4 cells and to determine their pathogenic potential at a single cell level by FC.

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“…Trop-2 surface expressionwas analyzed by flow cytometry as Zhang et al described previously. 33 Briefly, lung cancer cells were harvested and washed with FACS buffer (PBS with 5% FBS buffer and 0.1% NaN 3 ) for twice and then incubated with PE-anti human Trop-2 or isotype control antibodies for 30 min at 4 °C. Cells were then washed with FACS buffer and analyzed on a FACSCalibur flow cytometer with Cell Quest software (Becton Dickinson).…”

Section: Flow Cytometry (Facs)mentioning

confidence: 99%

Chemotherapy agents-induced immunoresistance in lung cancer cells could be reversed by trop-2 inhibition in vitro and in vivo by interaction with MAPK signaling pathway

Wang

Long

Dong

et al. 2013

Cancer Biology & Therapy

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Chemotherapy has been widely used in cancer treatment, but the prognosis of the cancer patients following chemotherapy has not been substantially improved. Alternative strategies such as immunotherapy and their combinations with chemotherapy are now being considered; however, the effects of chemotherapy on the immune responses of cancer cells are not fully understood. In the present studies, we reveal a potential link between chemotherapy and cancer immunoresistance, we first examined the effects of chemopreventive agent DDP on the expression of a cell surface glycopreotein Trop-2 in lung cancer cells, and found that DDP not only induce Trop-2 surface expression in human lung cancer cells, but also induce T-cell apoptosis effectively. In order to investigate the relationship between DDP-induced Trop-2 expression and T-cell apoptosis, we stably transfected A549 and PC14 lung cancer cells with Trop-2 shRNA, the DDP-induced Trop-2 surface expression was effectively decreased in stably transfected cell lines, but chemotherapeutic reagent-induced cell proliferation inhibition and apoptosis were increased through inhibition of the MAPK signaling pathway. In vivo animal experiments showed that Trop-2 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, DDP treatment exhibited a strong antitumor activity in the mice with Trop-2 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that DDP resistance in lung cancer cells could be induced through increased surface expression of Trop-2, which at least partially by interfering with MAPK pathway. These results provide novel insight into the function of Trop-2 and encourage the design and testing of approaches targeting this protein and its partners.

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The Net Effect of Costimulatory Blockers Is Dependent on the Subset and Activation Status of the Autoreactive T Cells

Cited by 6 publications

References 33 publications

The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen‐presenting cells

The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen‐presenting cells

Detection of cardiac myosin heavy chain-α-specific CD4 cells by using MHC class II/IAk tetramers in A/J mice

Chemotherapy agents-induced immunoresistance in lung cancer cells could be reversed by trop-2 inhibition in vitro and in vivo by interaction with MAPK signaling pathway

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